Epigenetic Regulation of the miR142-3p/Interleukin-6 Circuit in Glioblastoma

被引：85

作者：

Chiou, Guang-Yuh ^{[1
,6
]}

Chien, Chian-Shiu ^{[1
]}

Wang, Mong-Lien ^{[3
,5
]}

Chen, Ming-Teh ^{[4
,7
]}

Yang, Yi-Ping ^{[3
,5
]}

Yu, Yung-Luen ^{[10
,11
,12
]}

Chien, Yueh ^{[2
,6
]}

Chang, Yun-Ching ^{[2
,6
]}

Shen, Chiung-Chyi ^{[4
,8
]}

Chio, Chung-Ching ^{[9
]}

Lu, Kai-Hsi ^{[13
]}

Ma, Hsin-I ^{[14
,15
]}

Chen, Kuan-Hsuan ^{[3
,7
]}

Liu, Dean-Mo ^{[16
]}

Miller, Stephanie A. ^{[17
]}

Chen, Yi-Wei ^{[3
,4
,6
]}

Huang, Pin-I ^{[3
,4
,6
]}

Shih, Yang-Hsin ^{[4
,7
]}

Hung, Mien-Chie ^{[10
,11
,12
,17
]}

Chiou, Shih-Hwa ^{[2
,3
,4
,5
,6
]}

机构：

[1] Natl Yang Ming Univ, Inst Oral Biol, Taipei 112, Taiwan

[2] Natl Yang Ming Univ, Inst Pharmacol, Taipei 112, Taiwan

[3] Natl Yang Ming Univ, Inst Clin Med, Taipei 112, Taiwan

[4] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan

[5] Natl Yang Ming Univ, Canc Res Ctr, Taipei 112, Taiwan

[6] Taipei Vet Gen Hosp, Dept Med Res & Educ, Taipei 112, Taiwan

[7] Taipei Vet Gen Hosp, Dept Neurosurg, Taipei 112, Taiwan

[8] Taichung Vet Gen Hosp, Dept Neurosurg, Taichung 407, Taiwan

[9] Chi Mei Med Ctr, Dept Neurosurg, Tainan 710, Taiwan

[10] China Med Univ, Grad Inst Canc Biol, Taichung 404, Taiwan

[11] China Med Univ, Ctr Mol Med, Taichung 404, Taiwan

[12] Asia Univ, Dept Biotechnol, Taichung 413, Taiwan

[13] Cheng Hsin Gen Hosp, Dept Med Res & Educ, Taipei 112, Taiwan

[14] Triserv Gen Hosp, Dept Neurol Surg, Taipei 114, Taiwan

[15] Natl Def Med Ctr, Taipei 114, Taiwan

[16] Natl Chiao Tung Univ, Dept Mat Sci & Engn, Hsinchu 300, Taiwan

[17] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

来源：

MOLECULAR CELL | 2013年 / 52卷 / 05期

关键词：

PROMOTER METHYLATION; GENE-EXPRESSION; DNA METHYLATION; CANCER-CELLS; STEM-CELLS; GLIOMA; DIFFERENTIATION; MICRORNA-142-3P; INTERLEUKIN-6; MIGRATION;

D O I：

10.1016/j.molcel.2013.11.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related sternness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feed-back-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.

引用

页码：693 / 706

页数：14

共 40 条

[1] UHRF1 plays a role in maintaining DNA methylation in mammalian cells [J].